Compounds which modulate the CB2 receptor

ABSTRACT

Compounds of formula (I) are disclosed. Compounds according to the invention bind to and are agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treating pain.

APPLICATION DATA

This application claims benefit to U.S. provisional application Ser. No.60/986,004 filed Nov. 7, 2007.

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to novel compounds which modulate the CB2receptor and their use as medicaments.

2. Background Information

Cannabinoids are a group of about 60 distinct compounds found inCannabis sativa (also know as marijuana) with cannabinol, cannabidioland Δ⁹-tetrahydrocannabinol (THC) being the most representativemolecules. The therapeutic usage of Cannabis can be dated back toancient dynasties of China and includes applications for variousillnesses ranging from lack of appetite, emesis, cramps, menstrual pain,spasticity to rheumatism. The long history of Cannabis use has led tothe development of several pharmaceutical drugs. For example, Marinoland Cesamet which are based on THC and its analogous nabilone,respectively, are used as anti-emetic and appetite stimulant. Despite ofthe clinical benefits, the therapeutic usage of cannabis is limited byits psychoactive effects including hallucination, addiction anddependence. Mechoulam R, ed. Cannabinoids as Therapeutic Agents, BocaRaton, Fla.; CRC Press, 1986 provides a review of the medicinal use ofcannabis.

The physiological effects of cannabinoids are mediated by at least twoG-protein coupled receptors, CB1 and CB2. Autoradiographic studies havedemonstrated that CB1 receptors are expressed primarily in the centralnervous system, specifically in the cerebral cortex, hippocampus, basalganglia and cerebellum. They are also found to a lesser degree in thereproductive system and other peripheral tissues including that of theimmune system.

CB1 receptors regulate the release of neurotransmitters from thepre-synaptic neurons and are believed to mediate most of the euphoricand other central nervous system effects of cannabis, such asTHC-induced ring-catalepsy, hypomobility, and hypothermia, which werefound to be completely absent in mice with a deletion of the CB1 gene(Zimmer et al., Increased mortality, hypoactivity, and hypoalgesia incannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci USA. (1999)96:5780-5785.)

CB2 receptors are almost exclusively found in the immune system, withthe greatest density in the spleen. It is estimated that the expressionlevel of CB2 in the immune cells is about 10 to 100 times higher thanCB1. Within the immune system, CB2 is found in various cell types,including B cells, NK cells, monocytes, microglial cells, neutrophils, Tcells, dentritic cells and mast cells, suggesting that a wide range ofimmune functions can be regulated through CB2 modulators (Klein et al.,The cannabinoid system and immune system. J Leukoc Biol (2003)74:486-496). This is supported by the finding that the immunomodulatoryeffect of THC is absent in CB2 deficient mice (Bicklet et al.,Immunomodulation by cannabinoid is absent in mice deficient for thecannabinoid CB2 receptor. Eur J Pharmacol (2000) 396:141-149). CB2selective ligands have been developed and tested for their effects invarious imflammatory settings. For example, in animal models ofinflammation, CB2 selective agonists, inverse agonists and antagonistshave been shown to be effective in suppressing inflammation (Hanus etal., HU-308: a specific agonist for CB(2), a peripheral cannabinoidreceptor. Proc Natl Acad Sci USA. (1999) 96:14228-14233, Ueda et al.,Involvement of cannabinoid CB(2) receptor-mediated response and efficacyof cannabinoid CB(2) receptor inverse agonist, JTE-907, in cutaneousinflammation in mice. Eur J Pharmacol. (2005) 520:164-171 and Smith etal., The anti-inflammatory activities of cannabinoid receptor ligands inmouse peritonitis models Eur J Pharmacol. (2001) 432:107-119.).Furthermore, CB2 selective agonists inhibit disease severity andspasticity in animal models for multiple sclerosis (Baker et al.,Cannabinoids control spasticity and tremor in a multiple sclerosismodel. Nature (2000) 404:84-87. Arevalo-Martin et al., Therapeuticaction of cannabinoids in a murine model of multiple sclerosis JNeurosci. (2003) 23:2511-2516.). Taken together, these results supportthe notion that CB2 receptor modulators can be employed for thetreatment of medical conditions having an inflammatory component.

In addition to inflammation, CB2 agonists have been shown to inhibitpain and emesis. For instance, CB2 selective agonists blunt the painresponse induced by thermal or other stimuli (Malan et al., CB2cannabinoid receptor-mediated peripheral antinociception. Pain. (2001)93:239-45 and Nackley et al., Selective activation of cannabinoid CB(2)receptors suppresses spinal fos protein expression and pain behavior ina rat model of inflammation. Neuroscience (2003) 119:747-57.) CB2activation has also been demonstrated to inhibit neuropathic painresponse (Ibrahim et al., Activation of CB2 cannabinoid receptors byAM1241 inhibits experimental neuropathic pain: pain inhibition byreceptors not present in the CNS. Proc Natl Acad Sci USA. (2003)100:10529-33.) Finally, in contrast to the earlier data which did notfind CB2 in the brain, a recent article demonstrated the expression ofCB2 in the brain, at about 1.5% of the level in the spleen. CB2activation is shown by this article to be responsible for theanti-emetic effect of endocannabinoid (Van Sickle et al., Identificationand functional characterization of brainstem cannabinoid CB2 receptors.Science. 2005 310:329-332.) The foregoing results confirm that CB2agonists can be used for the treatment of inflammatory and neuropathicpain as well as emesis.

BRIEF SUMMARY OF THE INVENTION

The present invention provides novel compounds which bind to andmodulate the CB2 receptor. The invention also provides a method andpharmaceutical compositions for treating inflammation by way of theadministration of therapeutic amounts of these compounds. Lastly, theinvention provides a method and pharmaceutical compositions for treatingpain by way of the administration of therapeutic amounts of the newcompounds which are CB2 agonists.

DETAILED DESCRIPTION OF THE INVENTION

In its broadest generic aspect the invention provides compounds of theformula

wherein:

R¹ is C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl-C₀₋₂ alkyl- or heterocycle-C₀₋₂alkyl- wherein the heterocycle is chosen from tetrahydropyranyl,tetrahydrofuranyl, dioxanyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, piperidinyl, pyrrolidinyl,tetrahydrothienyl, sulfonalyl, tetrahydrothiopyranyl,1,1-dioxo-tetrahydrothiopyranyl, imidazolidinyl, pyrazolidinyl,oxetanyl, each R¹ is optionally substituted with 1 to 3 substituentschosen from halogen, C₁₋₅ alkyl, C₃₋₁₀ cycloalkyl, hydroxy and C₁₋₆alkoxy;

R² is hydrogen or C₁₋₅ alkyl;

or R¹ and R² together with the N atom to which they are attached form a3- to 6-membered heterocyclic ring optionally substituted with 1-3substituents chosen from C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl,hydroxyl, C₁₋₃ alkylaminocarbonyl, C₁₋₃ dialkylaminocarbonyl, C₁₋₃alkylcarbonyl, C₁₋₃ alkyl sulfonyl and halogen;

R³ is methyl, ethyl, or isopropyl;

R⁴ is H or methyl;

or

R³ and R⁴ together with the carbon they are attached to form a 3-4membered cycloalkyl ring;

R⁵ is C₁₋₁₀ alkyl optionally substituted by aryl or heteroaryl, or

R⁵ is furanyl, pyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,oxazolyl, imidazolyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, isoxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl,triazolyl, pyridinyl or benzothiazolyl each optionally independentlysubstituted with 1 to 3 substituents chosen from C₁₋₆ alkyl, C₁₋₅alkoxycarbonyl, cyano, halogen, carbocycle and heteroaryl, each R⁵ orit's substituents where possible are optionally partially or fullyhalogenated;

or a pharmaceutically acceptable salt thereof;

with the proviso that if R² is hydrogen then R¹ cannot be aryl.

In a first subgeneric aspect, the invention provides compounds of theformula I wherein,

R¹ is C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl-C₀₋₂ alkyl- or heterocycle-C₀₋₂alkyl- wherein the heterocycle is chosen from tetrahydropyranyl,tetrahydrofuranyl, dioxanyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, piperidinyl, pyrrolidinyl,tetrahydrothienyl, sulfonalyl, tetrahydrothiopyranyl,1,1-dioxo-tetrahydrothiopyranyl, imidazolidinyl, pyrazolidinyl,oxetanyl, each R¹ is optionally substituted with 1 to 3 substituentschosen from halogen, C₁₋₅ alkyl, C₃₋₁₀ cycloalkyl, hydroxy and C₁₋₆alkoxy;

R² is hydrogen or C₁₋₅ alkyl;

or R¹ and R² together with the N atom to which they are attached form a3- to 6-membered heterocyclic ring optionally substituted with 1-3substituents chosen from C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl,hydroxyl, C₁₋₃ alkylaminocarbonyl, C₁₋₃ dialkylaminocarbonyl, C₁₋₃alkylcarbonyl, C₁₋₃ alkyl sulfonyl and halogen;

R³ is methyl, ethyl, or isopropyl;

R⁴ is H or methyl;

or

R³ and R⁴ together with the carbon they are attached to form a 3-4membered cycloalkyl ring;

R⁵ is furanyl, pyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,oxazolyl, imidazolyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, isoxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl,triazolyl, pyridinyl or benzothiazolyl each optionally independentlysubstituted with 1 to 3 substituents chosen from C₁₋₆ alkyl, C₁₋₅alkoxycarbonyl, cyano, halogen, carbocycle and heteroaryl, each R⁵ orit's substituents where possible are optionally partially or fullyhalogenated.

In a further subgeneric aspect, the invention provides compounds of theformula I wherein,

R¹ is C₁₋₅ alkyl, C₃₋₆ cycloalkyl-C₀₋₂ alkyl- or heterocycle-C₀₋₂ alkyl-wherein the heterocycle is chosen from tetrahydropyranyl,tetrahydrofuranyl, dioxanyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholinyl, piperidinyl, pyrrolidinyl,tetrahydrothienyl, sulfonalyl, tetrahydrothiopyranyl,1,1-dioxo-tetrahydrothiopyranyl, imidazolidinyl, pyrazolidinyl,oxetanyl, and morpholinyl, each R¹ is optionally independentlysubstituted with 1 to 3 substituents chosen from halogen, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, hydroxy and C₁₋₆ alkoxy;

R¹ and R² together with the N atom to which they are attached formmorpholinyl, piperidinyl, azetidinyl or pyrrolidinyl homopiperidinyl,thiomorpholinyl, 1,1-dioxo-1λ⁶-thiomorpholinyl, piperazinyl, eachoptionally substituted with 1-3 substituents chosen from C₁₋₃ alkyl,C₁₋₃ alkoxy, C₃₋₆ cycloalkyl, C₁₋₃ alkylaminocarbonyl, C₁₋₃dialkylaminocarbonyl, C₁₋₃ alkylcarbonyl, C₁₋₃ alkyl sulfonyl andhalogen;

R⁵ is furanyl, pyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,oxazolyl, imidazolyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, triazolyl,pyridinyl or benzothiazolyl each R⁵ substituent is further optionallysubstituted with 1 to 3 substituents chosen from C₁₋₅ alkyl, C₁₋₅alkoxycarbonyl, cyano, halogen, phenyl, C₃₋₁₀ cycloalkyl, furanyl,pyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl,imidazolyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, triazolyl, pyridinyl,and benzothiazolyl, each R⁵ or it's substituents where possible areoptionally partially or fully halogenated.

In a further subgeneric aspect, the invention provides compounds of theformula I wherein,

R¹ is C₁₋₅ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylmethyl,tetrahydropyranyl, tetrahydrofuranyl or morpholinyl, each optionallyindependently substituted with 1 to 3 substituents chosen from halogen,C₁₋₃ alkyl, C₃₋₆ cycloalkyl and C₁₋₃ alkoxy;

R⁵ is furanyl, pyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,oxazolyl, imidazolyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, triazolyl,pyridinyl or benzothiazolyl each R⁵ substituent is further optionallysubstituted with 1 to 3 substituents chosen from C₁₋₅ alkyl, C₁₋₅alkoxycarbonyl, cyano, halogen, phenyl, C₃₋₆ cycloalkyl and pyridinyl,each R⁵ or it's substituents where possible are optionally partially orfully halogenated.

In a further subgeneric aspect, the invention provides compounds of theformula I wherein,

R¹ is C₁₋₅ alkyl, C₃₋₆ cycloalkyl, cyclohexylmethyl ortetrahydropyranyl, each optionally independently substituted with 1 to 3substituents chosen from halogen, C₁₋₃ alkyl, C₃₋₆ cycloalkyl and C₁₋₄alkoxy;

R¹ and R² together with the N atom to which they are attached formmorpholinyl, piperidinyl, azetidinyl or pyrrolidinyl each optionallysubstituted with 1-3 substituents chosen from C₁₋₃ alkyl, C₁₋₃ alkoxy,C₃₋₆ cycloalkyl, C₁₋₃ alkylaminocarbonyl, C₁₋₃ dialkylaminocarbonyl,C₁₋₃ alkylcarbonyl, C₁₋₃ alkyl sulfonyl and halogen

In a further subgeneric aspect, the invention provides compounds of theformula I wherein,

R¹ is C₁₋₅ alkyl, C₃₋₆ cycloalkyl or tetrahydropyranyl, each optionallyindependently substituted with 1 to 3 substituents chosen from halogen,C₁₋₃ alkyl, C₁₋₃ alkoxy and C₃₋₆ cycloalkyl.

In another subgeneric aspect, the invention provides compounds of theformula I:

wherein for the formula (I)

is chosen members of column A in Table I, and

is chosen members of column B in Table I:

TABLE I A B

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides compounds in Table IIwhich can be made in view of the general schemes, examples and methodsknown in the art.

TABLE II

N-(5-tert-Butyl-isoxazol-3-yl)-2-dimethylsulfamoyl-2-methyl-propionamide

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(2-methyl-piperidine-1-sulfonyl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-(isopropyl-methyl-sulfamoyl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(5 -tert-butyl-isoxazol-3-yl)-2-methyl-propionamide

N-(5 -tert-Butyl-isoxazol-3 -yl)-2-methyl-2-(pyrrolidine-1-sulfonyl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-cyclopropylsulfamoyl-2-methyl-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-cyclohexylsulfamoyl-2-methyl-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(piperidine-1-sulfonyl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-cyclopentylsulfamoyl-2-methyl-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-(4-methoxy-piperidine-1-sulfonyl)-2-methyl-propionamide

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-cyclopropylsulfamoyl-2-methyl-propionamide

2-Methyl-2-(piperidine-1-sulfonyl)-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

2-(4-Methoxpiperidine-1-sulfonyl)2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-isopropylsulfamoyl-2-methyl-propionamide

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-isopropylsulfamoyl-2-methyl-propionamide

2-Cyclopropylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

2-Cyclohexylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

2-Cyclopentylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-ethylsulfamoyl-2- methyl-propionamide

N-(4-tert-Butyl-thiazol-2-yl)-2-ethylsulfamoyl-2- methyl-propionamide

2-Ethylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

2-Ethylsulfamoyl-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-butylsulfamoyl-2- methyl-propionamide

2-Butylsulfamoyl-N-(4-tert-butyl-thiazol-2-yl)-2- methyl-propionamide

2-Butylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

2-Butylsulfamoyl-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-(2-ethoxy-ethylsulfamoyl)-2-methyl-propionamide

N-(4-tert-Butyl-thiazol-2-yl)-2-(2-ethoxy-ethylsulfamoyl)-2-methyl-propionamide

2-(2-Ethoxy-ethylsulfamoyl)-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)-propionamide

N-(4-tert-Butyl-thiazol-2-yl)-2-methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)-propionamide

2-Methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

2-Meth-2-(tetrahydro-pyran-4-ylsulfamoyl)-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2- propylsulfamoyl-propionamide

2-(2-Ethoxy-ethylsulfamoyl)-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-(4,4-difluoro-piperidine-1-sulfonyl)-2-methyl-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-(3,3-difluoro-azetidine-1-sulfonyl)-2-methyl-propionamide

(R)-N-(5-tert-Butyl-isoxazol-3-yl)-2-(3-fluoro-pyrrolidine-1-sulfonyl)-2-methyl-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-(butyl-methyl-sulfamoyl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-[4-(4-chloro-phenyl)-thiazol-2-yl]-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(4-tert-butyl-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-[4-(4-fluoro-phenyl)-thiazol-2-yl]-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(5-tert-butyl-4-methyl-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-propyl-isoxazol-5-yl)-propionamide

2-(Azetidine-1-sulfonyl)-N-[3-(2,2-dimethyl-propyl)-isoxazol-5-yl]-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-benzothiazol-2-yl-2- methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(4-ethyl-pyridin-2-yl)-2- methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(5-phenyl-[1,2,4]thiadiazol-3-yl)-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-thiophen-2-yl-thiazol-2-yl)-propionamide

2-(Azetidine-1-sulfonyl)-N-(5-ethyl-4-phenyl-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(4-cyclohexyl-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-trifluoromethyl-phenyl)-propionamide

2-(Azetidine-1-sulfonyl)-N-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(4-tert-butyl-phenyl)-2- methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-phenethyl- propionamide

2-(Azetidine-1-sulfonyl)-N-[2-(2-chloro-phenyl)-ethyl]-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(3,3-dimethyl-butyl)-2- methyl propionamide

2-(Azetidine-1-sulfonyl)-N-(6-fluoro-benzothiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-[2-(3-chloro-phenyl)-ethyl]-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-trifluoromethyl-phenyl)-propionamide

2-(Azendine-1-sulfonyl)-N-(3-tert-butyl-phenyl)-2- methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(3-fluoro-4-trifluoromethyl-phenyl)-2-methyl-propionamide

2-(Azendine-1-sulfonyl)-N-(4-tert-butyl-5-cyano-thiazol-2-yl)-2-methyl-propionamide

2-(Azendine-1-sulfonyl)-2-methyl-N-(4-pyridin-3-yl-thiazol-2-yl)-propionarnide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-pyridin-2-yl-thiazol-2-yl)-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-pyridin-4-yl-thiazol-2-yl)-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-trifluorornethyl-thiazol-2-yl)-propionamide

2-(Azetidine-1-sulfonyl)-2-rnethyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide

2-(Azetidine-1-sulfonyl)-N-(3-sec-butyl-isoxazol-5-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(3-isopropyl-isoxazol-5-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-propionamide

2-[2-(Azetidine-1-sulfonyl)-2-methyl-propionylamino]-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester

2-(Azetidine-1-sulfonyl)-N-(4,5-diphenyl-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(4,5-dimethyl-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-phenyl-isoxazol-5-yl)-propionamide

2-(Azetidine-1-sulfonyl)-N-(4-cyclopropyl-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(2-tert-butyl-pyridin-4-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-thiophen-2-yl-isoxazol-5-yl)-propionamide

2-(Azetidine-1-sulfonyl)-N-[4-(4-fluoro-phenyl)-5-methyl-thiazol-2-yl]-2-methyl-propionamide

N(3-tert-Butyl-isoxazol-5yl)2-methyl-2 -(morpholine-4-sulfonyl)-propionanide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)-propionamide2-Methyl-2-(morpholine-4-sulfonyl)-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)-propionamide

N-(5-tert-Butyl-[1,3,4]thiadiazol-2-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamide

N-(3-tert-Butyl-isothiazol-5-yl)-2-(3-fluoro-pyrrolidine-1-sulfonyl)-2-methyl-propionamide

2-(3-Fluoro-pyrrolidine-1-sulfonyl)-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide

N-(3-Cyclopentyl-isoxazol-5-yl)-2-(3(R)-fluoro-pyrrolidine-1-sulfonyl)-2-methyl-propionamide

2-(3-Fluoro-pyrrolidine-1-sulfonyl)-2-methyl-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)-propionamide

2-(3-Fluoro-pyrrolidine-1-sulfonyl)-2-methyl-N-(4-trifluoromethyl-thiazol-2-yl)-propionamideor a pharmaceutically acceptable salt thereof.

Of the above compounds, the following are preferred CB2 agonists:

TABLE III Compound CB2 EC50 (nM)N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-y1)-2-methyl-2- 79(morpholine-4-sulfonyl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(2-methyl- 97piperidine-l-sulfony1)-propionamide2-(Azetidine-1-sulfonyl)-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl- 3.6propionamideN-(5-tert-Butyl-isoxazol-3-y1)-2-methyl-2-(pyrrolidine-1-sulfonyl)- 1.3propionamide N-(5-tert-Butyl-isoxazol-3-yl)-2-cyclopropylsulfamoyl-2- 58methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-cyclohexylsulfamoyl-2- 2.4methyl-propionamideN-(5-tert-Butyl-isoxazol-3-y1)-2-methyl-2-(piperidine-1- 6.5sulfonyl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-cyclopentylsulfamoyl-2- 13methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-butylsulfamoyl-2-methyl- 10propionamide 2-Butylsulfamoyl-N-(4-tert-butyl-thiazol-2-yl)-2-methyl- 32propionamide N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2- 33propylsulfamoyl-propionamideN-(4-tert-Butyl-thiazol-2-yl)-2-methyl-2-(methyl-phenyl- 42sulfamoyl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-(4,4-difluoro-piperidine- 2.51-sulfonyl)-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-y1)-2-(3,3-difluoro-azetidine-1- 5.0sulfonyl)-2-methyl-propionamide(R)-N-(5-tert-Butyl-isoxazol-3-y1)-2-(3-fluoro-pyrrolidine- 5.71-sulfonyl)-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(morpholine-4- 47sulfonyl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-(butyl-methyl-sulfamoyl)- 1.72-methyl-propionamide2-(Azetidine-l-sulfonyl)-N-[4-(4-chloro-phenyl)-thiazol-2- 8.9yl]-2-methyl-propionamide2-(Azetidine-l-sulfonyl)-N-(4-tert-butyl-thiazol-2-y1)-2- 14methyl-propionamide2-(Azetidine-l-sulfonyl)-N-[4-(4-fluoro-phenyl)-thiazol-2- 19yl]-2-methyl-propionamide2-(Azetidine-l-sulfonyl)-N-(5-tert-butyl-4-methyl-thiazol- 2.52-yl)-2-methyl-propionamide2-(Azetidine-l-sulfonyl)-N-(3-tert-butyl-isoxazol-5-y1)-2- 20methyl-propionamide2-(Azetidine-l-sulfonyl)-N-benzothiazol-2-y1-2-methyl- 26 propionamide2-(Azetidine-l-sulfonyl)-2-methyl-N-(5-phenyl- 72[1,2,4]thiadiazol-3-y1)-propionamide2-(Azetidine-l-sulfonyl)-2-methyl-N-(4-thiophen-2-yl- 41thiazol-2-yl)-propionamide2-(Azetidine-l-sulfonyl)-N-(5-ethyl-4-phenyl-thiazol-2-yl)-2-methyl- 6.6propionamide 2-(Azetidine-l-sulfonyl)-N-(4-cyclohexyl-thiazol-2-y1)-2-22 methyl-propionamide2-(Azetidine-l-sulfonyl)-N-(4-tert-butyl-phenyl)-2-methyl- 3.1propionamide 2-(Azetidine-l-sulfonyl)-N-(3-tert-butyl-phenyl)-2-methyl-17 propionamide2-(Azetidine-l-sulfonyl)-N-(3-sec-butyl-isoxazol-5-y1)-2- 14methyl-propionamide2-(Azetidine-l-sulfonyl)-N-(3-isopropyl-isoxazol-5-y1)-2- 108methyl-propionamide2-(Azetidine-l-sulfonyl)-2-methyl-N-(4,5,6,7-tetrahydro- 62benzothiazol-2-yl)-propionamide2-(Azetidine-l-sulfonyl)-N-(2-fluoro-4-trifluoromethyl- 86phenyl)-2-methyl-propionamide2-(Azetidine-l-sulfonyl)-N-(2-tert-butyl-pyridin-4-y1)-2- 37methyl-propionamide2-(Azetidine-l-sulfonyl)-N-[4-(4-fluoro-phenyl)-5-methyl- 17thiazol-2-y1]-2-methyl-propionamideN-(3-tert-Butyl-isoxazol-5-yl)-2-methyl-2-(morpholine-4- 15sulfonyl)-propionamide 2-(Azetidine-l-sulfony1)-2-methyl-N-(5-phenyl-4H-11 [1,2,4]triazol-3-y1)-propionamide2-Methyl-2-(morpholine-4-sulfonyl)-N-(5-phenyl-4H- 86[1,2,4]triazol-3-y1)-propionamideN-(3-tert-Butyl-isothiazol-5-y1)-2-(3-fluoro-pyrrolidine-1- 83sulfonyl)-2-methyl-propionamide2-(3-Fluoro-pyrrolidine-l-sulfonyl)-2-methyl-N-(5-phenyl- 5.14H-[1,2,4]triazol-3-y1)-propionamide

In all the compounds disclosed hereinabove in this application, in theevent the nomenclature is in conflict with the structure, it shall beunderstood that the compound is defined by the structure.

The invention also relates to pharmaceutical preparations, containing asactive substance one or more compounds of formula (I), or thepharmaceutically acceptable derivatives thereof, optionally combinedwith conventional excipients and/or carriers.

Compounds of the invention also include their isotopically-labelledforms. An isotopically-labelled form of an active agent of a combinationof the present invention is identical to said active agent but for thefact that one or more atoms of said active agent have been replaced byan atom or atoms having an atomic mass or mass number different from theatomic mass or mass number of said atom which is usually found innature. Examples of isotopes which are readily available commerciallyand which can be incorporated into an active agent of a combination ofthe present invention in accordance with well established procedures,include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, ¹⁸F, and ³⁶Cl, respectively. An active agent of a combination ofthe present invention, a prodrug thereof, or a pharmaceuticallyacceptable salt of either which contains one or more of theabove-mentioned isotopes and/or other isotopes of other atoms iscontemplated to be within the scope of the present invention.

The invention includes the use of any compounds of described abovecontaining one or more asymmetric carbon atoms may occur as racematesand racemic mixtures, single enantiomers, diastereomeric mixtures andindividual diastereomers. Isomers shall be defined as being enantiomersand diastereomers. All such isomeric forms of these compounds areexpressly included in the present invention. Each stereogenic carbon maybe in the R or S configuration, or a combination of configurations.

Some of the compounds of formula (I) can exist in more than onetautomeric form. The invention includes methods using all suchtautomers.

All terms as used herein in this specification, unless otherwise stated,shall be understood in their ordinary meaning as known in the art. Forexample, “C₁₋₄alkoxy” is a C₁₋₄alkyl with a terminal oxygen, such asmethoxy, ethoxy, propoxy, butoxy. All alkyl, alkenyl and alkynyl groupsshall be understood as being branched or unbranched where structurallypossible and unless otherwise specified. Other more specific definitionsare as follows:

Carbocycles include hydrocarbon rings containing from three to twelvecarbon atoms. These carbocycles may be either aromatic or non-aromaticring systems. The non-aromatic ring systems may be mono- orpolyunsaturated. Preferred carbocycles include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl,benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl,decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certainterms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be usedinterchangeably.

The term “heterocycle” refers to a stable nonaromatic 4-8 membered (butpreferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 memberedbicyclic heterocycle radical which may be either saturated orunsaturated. Each heterocycle consists of carbon atoms and one or more,preferably from 1 to 4 heteroatoms chosen from nitrogen, oxygen andsulfur. The heterocycle may be attached by any atom of the cycle, whichresults in the creation of a stable structure.

The term “heteroaryl” shall be understood to mean an aromatic 5-8membered monocyclic or 8-11 membered bicyclic ring containing 1-4heteroatoms such as N, O and S.

Unless otherwise stated, heterocycles and heteroaryl include but are notlimited to, for example furanyl, pyranyl, benzoxazolyl, benzothiazolyl,benzimidazolyl, tetrahydropyranyl, dioxanyl, tetrahydrofuranyl,oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl,thienyl, thiadiazolyl, thiomorpholinyl, 1,1-Dioxo-1λ⁶-thiomorpholinyl,morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,pyrrolidinyl, piperidinyl, piperazinyl, purinyl, quinolinyl,Dihydro-2H-quinolinyl, isoquinolinyl, quinazolinyl, indazolyl,thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl, benzofuranyl,benzopyranyl and benzodioxolyl.

The term “heteroatom” as used herein shall be understood to mean atomsother than carbon such as O, N, S and P.

In all alkyl groups or carbon chains one or more carbon atoms can beoptionally replaced by heteroatoms: O, S or N, it shall be understoodthat if N is not substituted then it is NH, it shall also be understoodthat the heteroatoms may replace either terminal carbon atoms orinternal carbon atoms within a branched or unbranched carbon chain. Suchgroups can be substituted as herein above described by groups such asoxo to result in definitions such as but not limited to: alkoxycarbonyl,acyl, amido and thioxo.

The term “aryl” as used herein shall be understood to mean aromaticcarbocycle or heteroaryl as defined herein. Each aryl or heteroarylunless otherwise specified includes it's partially or fully hydrogenatedderivative. For example, quinolinyl may include decahydroquinolinyl andtetrahydroquinolinyl, naphthyl may include it's hydrogenated derivativessuch as tetrahydranaphthyl. Other partially or fully hydrogenatedderivatives of the aryl and heteroaryl compounds described herein willbe apparent to one of ordinary skill in the art.

As used herein, “nitrogen” and “sulfur” include any oxidized form ofnitrogen and sulfur and the quaternized form of any basic nitrogen. Forexample, for an —S—C₁₋₆ alkyl radical, unless otherwise specified, thisshall be understood to include —S(O)—C₁₋₆ alkyl and —S(O)₂—C₁₋₆ alkyl.

The term “alkyl” refers to a saturated aliphatic radical containing fromone to ten carbon atoms or a mono- or polyunsaturated aliphatichydrocarbon radical containing from two to twelve carbon atoms. Themono- or polyunsaturated aliphatic hydrocarbon radical containing atleast one double or triple bond, respectively. “Alkyl” refers to bothbranched and unbranched alkyl groups. It should be understood that anycombination term using an “alk” or “alkyl” prefix refers to analogsaccording to the above definition of “alkyl”. For example, terms such as“alkoxy”, “alkylhio” refer to alkyl groups linked to a second group viaan oxygen or sulfur atom. “Alkanoyl” refers to an alkyl group linked toa carbonyl group (C═O).

The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine, preferablyfluorine. The definitions “partially or fully halogenated”; partially orfully fluorinated; “substituted by one or more halogen atoms”, includesfor example, mono, di or tri halo derivatives on one or more carbonatoms. For alkyl, a nonlimiting example would be —CH₂CHF₂, —CF₃ etc.

Each alkyl, carbocycle, heterocycle or heteroaryl, or the analogsthereof, described herein shall be understood to be optionally partiallyor fully halogenated.

The compounds of the invention are only those which are contemplated tobe ‘chemically stable’ as will be appreciated by those skilled in theart. For example, a compound which would have a ‘dangling valency’, or a‘carbanion’ are not compounds contemplated by the inventive methodsdisclosed herein.

The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (I). A “pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable salt or ester, or any othercompound which, upon administration to a patient, is capable ofproviding (directly or indirectly) a compound useful for the invention,or a pharmacologically active metabolite or pharmacologically activeresidue thereof. A pharmacologically active metabolite shall beunderstood to mean any compound of the invention capable of beingmetabolized enzymatically or chemically. This includes, for example,hydroxylated or oxidized derivative compounds of the formula (I).

Pharmaceutically acceptable salts include those derived frompharmaceutically acceptable inorganic and organic acids and bases.Examples of suitable acids include hydrochloric, hydrobromic, sulfuric,nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic,salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric,methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric andbenzenesulfonic acids. Other acids, such as oxalic acid, while notthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsand their pharmaceutically acceptable acid addition salts. Salts derivedfrom appropriate bases include alkali metal (e.g., sodium), alkalineearth metal (e.g., magnesium), ammonium and N—(C₁-C₄ alkyl)₄ ⁺ salts.

In addition, within the scope of the invention is use of prodrugs ofcompounds of the formula (I). Prodrugs include those compounds that,upon simple chemical transformation, are modified to produce compoundsof the invention. Simple chemical transformations include hydrolysis,oxidation and reduction. Specifically, when a prodrug is administered toa patient, the prodrug may be transformed into a compound disclosedhereinabove, thereby imparting the desired pharmacological effect.

The compounds of formula I may be made using the general syntheticmethods described below, which also constitute part of the invention.

General Synthetic Methods

The invention also provides processes for making compounds of Formula(I). In all methods, unless specified otherwise, R¹, R², R³, R⁴ and R⁵in the formulas below shall have the meaning of R¹, R², R³, R⁴ and R⁵ inFormula (I) of the invention described herein above. Optimum reactionconditions and reaction times may vary depending on the particularreactants used. Unless otherwise specified, solvents, temperatures,pressures, and other reaction conditions may be readily selected by oneof ordinary skill in the art. Specific procedures are provided in theSynthetic Examples section. Typically, reaction progress may bemonitored by thin layer chromatography (TLC), if desired, andintermediates and products may be purified by chromatography on silicagel and/or by recrystallization.

The examples which follow are illustrative and, as recognized by oneskilled in the art, particular reagents or conditions could be modifiedas needed for individual compounds without undue experimentation.Starting materials and intermediates used, in the methods below, areeither commercially available or easily prepared from commerciallyavailable materials by those skilled in the art.

Further modification of the initial product of formula (I) by methodsknown in the art and illustrated in the Examples below, may be used toprepare additional compounds of this invention.

Compounds of formula (I) may be synthesized by the method outlined inscheme 1.

As illustrated in scheme 1, reaction of a bromo-ester of formula II witha reagent such as potassium thioacetate, in a suitable solvent, providesa sulfanyl compound of formula III. Reaction of the sulfanyl compound offormula III with chlorine affords the corresponding sulfinyl chloride.Reaction of the sulfinyl chloride with an amine R¹R²NH, in a suitablesolvent, provides a compound of formula IV. Oxidation of the compound offormula IV with an oxidizing agent such as meta-chloroperbenzoic acid,provides the corresponding sulfone of formula V. Hydrolysis of thesulfone V with a reagent such as potassium trimethylsilanolate, in asuitable solvent, provides the corresponding acid of formula VI.

Reaction of the acid of formula VI with thionyl chloride or oxalylchloride affords the corresponding acid chloride which is then reactedwith an amine R⁵NH₂, in a suitable solvent, in the presence of asuitable base, to provide a compound of formula (I). Alternatively, theacid of formula VI may also be coupled with an amine R⁵NH₂ understandard coupling conditions, to provide a compound of formula (I).Standard peptide coupling reactions known in the art (see for example M.Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) maybe employed in these syntheses. An example of suitable couplingconditions is treatment of a solution of the carboxylic acid in asuitable solvent such as DMF with EDC, HOBT, and a base such asdiisopropylethylamine, followed by the desired amine.

Further modification of the initial product of formula (I) by methodsknown in the art and illustrated in the Examples below, may be used toprepare additional compounds of this invention.

EXPERIMENTAL PROCEDURES Method Synthesis ofN-(5-tert-butyl-isoxazol-3-yl)-2-cyclopentylsulfamoyl-2-methyl-propionamide(Example 5 in Table 4)

Step 1: Synthesis of 2-acetylsulfanyl-2-methyl-propionic acid ethylester

To a solution of ethyl α-bromoisobutyrate (62 g, 0.32 mol) inN,N-dimethylformamide (500 mL) at room temperature is added potassiumthioacetate (72 g, 0.63 mol). The reaction is stirred for 16 h and thenconcentrated under reduced pressure. The residue is diluted with a 2Maqueous hydrochloric acid solution (500 mL) and extracted with ethylacetate (3×500 mL). The organic fractions are combined, washed withbrine (300 mL), dried (MgSO₄), filtered and concentrated under reducedpressure. Purification by chromatography on silica eluting withheptanes/dichloromethane provides the title compound, m/z 191 [M+H⁺].

Step 2: Synthesis of 2-(azetidine-1-sulfinyl)-2-methyl-propionic acidethyl ester

Chlorine gas is bubbled through a biphasic mixture of2-acetylsulfanyl-2-methyl-propionic acid ethyl ester (5.0 g, 26 mmol) indichloromethane (50 mL) and water (50 mL) at 10° C. for 10 min. Afterthis time, the organic phase is separated, dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude sulfinyl chloride isre-dissolved in dichloromethane (50 mL) and N,N-diisopropylethylamine(4.58 mL, 26 mmol) and azetidine (1.5 g, 26 mmol) are introduced. Thereaction is stirred at room temperature for 1 h and then concentratedunder reduced pressure. Purification by chromatography on silica elutingwith ethyl acetate/heptanes provides the title compound, m/z 220 [M+H⁺]

Using a similar procedure, the sulfinamides listed in Table IV aresynthesized.

TABLE IV m/z Structure Name [M + H⁺]

2-Dimethylsulfinamoyl-2-methyl-propionic acid ethyl ester 208

2-Methyl-2-(morpholine-4-sulfinyl)- propionic acid ethyl ester 250

2-Methyl-2-(2-methyl-piperidine-1- sulfinyl)-propionic acid ethyl ester262

2-(Isopropyl-methyl-sulfinamoyl)-2-methyl- propionic acid ethyl ester220

2-(Azetidine-1-sulfinyl)-2-methyl-propionic acid ethyl ester 220

2-Methyl-2-(pyrrolidine-1-sulfinyl)- propionic acid ethyl ester 234

2-Cyclopropylsulfinamoyl-2-methyl- propionic acid ethyl ester 220

2-Cyclohexylsulfinamoyl-2-methyl- propionic acid ethyl ester 262

2-Methyl-2-(piperidine-1-sulfinyl)-propionic acid ethyl ester 248

2-Cyclopentylsulfinamoyl-2-methyl- propionic acid ethyl ester 248

2-(4-Methoxy-piperidine-1-sulfinyl)-2- methyl-propionic acid ethyl ester278

2-Ethylsulfinamoyl-2-methyl-propionic acid ethyl ester 208

2-Butylsulfinamoyl-2-methyl-propionic acid ethyl ester 236

2-(2-Ethoxy-ethylsulfinamoyl)-2-methyl- propionic acid ethyl ester 252

2-Methyl-2-(tetrahydro-pyran-4- ylsulfinamoyl)-propionic acid ethylester 264

2-Methyl-2-propylsulfinamoyl-propionic acid ethyl ester 222

2-(4,4-Difluoro-piperidine-1-sulfinyl)-2- methyl-propionic acid ethylester 284

2-(3,3-Difluoro-azetidine-1-sulfinyl)-2- methyl-propionic acid ethylester 256

(R)-2-(3-Fluoro-pyrrolidine-1-sulfinyl)-2- methyl-propionic acid ethylester 252

2-Isopropylsulfinamoyl-2-methyl-propionic acid ethyl ester 222

2-(Butyl-methyl-sulfinamoyl)-2-methyl- propionic acid ethyl ester 250

Step 3: Synthesis of 2-(azetidine-1-sulfonyl)-2-methyl-propionic acidethyl ester

To a solution of 2-(azetidine-1-sulfinyl)-2-methyl-propionic acid ethylester (4.62 g, 21 mmol) in dichloromethane (100 mL) at room temperatureis added meta-chloroperbenzoic acid (5.46 g, 32 mmol). The reaction isstirred for 1 h before Ambersep 900-OH resin (2.9 g) is introduced. Thesuspension is shaken for 2 h and then filtered. The filtrate isconcentrated under reduced pressure and the residue is re-dissolved indichloromethane (50 mL), washed with a saturated solution of sodiumbicarbonate (50 mL) and the solvent is concentrated under reducedpressure to provide the title compound as an orange oil. This oil isused without further purification, m/z 236 [M+H⁺].

Using a similar procedure, the sulfonamides listed in Table V aresynthesized.

TABLE V m/z [M + H⁺] Structure Name or ¹H-NMR

2-Dimethylsulfamoyl-2-methyl-propionic acid ethyl ester 224, 241 [M +H₂O⁺]

2-Methyl-2-(morpholine-4-sulfonyl)- propionic acid ethyl ester 266

2-Methyl-2-(2-methyl-piperidine-1- sulfonyl)-propionic acid ethyl ester278

2-(Isopropyl-methyl-sulfamoyl)-2- methyl-propionic acid ethyl ester 252

2-(Azetidine-1-sulfonyl)-2-methyl- propionic acid ethyl ester 236

2-Methyl-2-(pyrrolidine-1-sulfonyl)- propionic acid ethyl ester 250

2-Cyclopropylsulfamoyl-2-methyl- propionic acid ethyl ester 1H NMR (400MHz- CHLOROFORM- d): δ ppm 0.72- 0.77 (4H, m), 1.32 (3H, t, J = 7.3 Hz),1.70 (6H, s), 2.62 (1H, m), 4.26 (2H, q, J = 7.3 Hz), 5.06 (1H, s)

2-Cyclohexylsulfamoyl-2-methyl- propionic acid ethyl ester 278

2-Methyl-2-(piperidine-1-sulfonyl)- propionic acid ethyl ester 264

2-Cyclopentylsulfamoyl-2-methyl- propionic acid ethyl ester 264

2-(4-Methoxy-piperidine-1-sulfonyl)-2- methyl-propionic acid ethyl ester294

2-Ethylsulfamoyl-2-methyl-propionic acid ethyl ester 224

2-Butylsulfamoyl-2-methyl-propionic acid ethyl ester 252

2-(2-Ethoxy-ethylsulfamoyl)-2-methyl- propionic acid ethyl ester 268

2-Methyl-2-(tetrahydro-pyran-4- ylsulfamoyl)-propionic acid ethyl ester250

2-Methyl-2-propylsulfamoyl-propionic acid ethyl ester 238

2-(4,4-Difluoro-piperidine-1-sulfonyl)-2- methyl-propionic acid ethylester 300

2-(3,3-Difluoro-azetidine-1-sulfonyl)-2- methyl-propionic acid ethylester 272

(R)-2-(3-Fluoro-pyrrolidine-1-sulfonyl)-2- methyl-propionic acid ethylester 268

2-Isopropylsulfamoyl-2-methyl-propionic acid ethyl ester 238

2-(Butyl-methyl-sulfamoyl)-2-methyl- propionic acid ethyl ester 266

Step 4: Synthesis of 2-(azetidine-1-sulfonyl)-2-methyl-propionic acid

To a solution of 2-(azetidine-1-sulfonyl)-2-methyl-propionic acid ethylester (5.0 g, 21 mmol) in tetrahydrofuran (200 mL) at room temperatureis added potassium trimethylsilanolate (8.2 g, 64 mmol). The reaction isstirred for 1 h. After this time, the mixture is diluted with a solutionof 1N aqueous hydrochloric acid (50 mL) and extracted withdichloromethane (250 mL). The organic phase is dried (MgSO₄), filteredand concentrated under reduced pressure to provide the title compound asa white solid, m/z 208 [M+H⁺].

Using a similar procedure, the carboxylic acids listed in Table VI aresynthesized.

TABLE VI m/z [M + H⁺] or Structure Name ¹H-NMR

2-Dimethylsulfamoyl-2-methyl- propionic acid 196, 213 [M + H₂O⁺]

2-Methyl-2-(morpholine-4-sulfonyl)- propionic acid 238

2-Methyl-2-(2-methyl-piperidine-1- sulfonyl) propionic acid 1H NMR (400MHz- DMSO-d6): δ ppm 1.14 (3H, d, J = 6.8 Hz), 1.40 (6H, s), 1.35-1.70(6H, m), 2.99 (1H, dt, J = 12.2, 2.0 Hz), 3.34 (1H, m), 3.88 (1H, m)

2-(Isopropyl-methyl-sulfamoyl)-2- methyl-propionic acid 1H NMR (360 MHz-DMSO-d6): δ ppm 1.15 (6H, d, J = 6.6 Hz), 1.48 (6H, s), 2.72 (3H, s),3.96 (1 H, m, J = 6.6 Hz)

2-(Azetidine-1-sulfonyl)-2-methyl- propionic acid 208

2-Methyl-2-(pyrrolidine-1-sulfonyl)- propionic acid 222

2-Cyclopropylsulfamoyl-2-methyl- propionic acid 1H NMR (400 MHz-DMSO-d6): δ ppm 0.49-0.51 (4H, m), 1.45 (6H, s), 2.50 (1H, m), 7.60 (1H,br s)

2-Cyclohexylsulfamoyl-2-methyl- propionic acid 1H NMR (400 MHz-DMSO-d6): δ ppm 0.99 (1H, m), 1.11-1.16 (4H, m), 1.39 (6H, s), 1.42-1.47 (1H, m), 1.60 (2H, m), 1.78 (2H, m), 2.98 (1H, m), 7.10 (1H, br s)

2-Methyl-2-(piperidine-1-sulfonyl)- propionic acid 1H NMR (400 MHz-DMSO-d6): δ ppm 1.40 (6H, s), 1.45 (6H, m), 3.20 (4H, m)

2-Cyclopentylsulfamoyl-2-methyl- propionic acid 236

2-(4-Methoxy-piperidine-1-sulfonyl)-2- methyl-propionic acid 266

2-Ethylsulfamoyl-2-methyl-propionic acid 1H NMR (400 MHz- DMSO-d6): δppm 1.00 (3H, t, J = 7.3 Hz), 1.40 (6H, s), 2.97 (2H, q, J = 7.3 Hz),7.10 (1H, br s)

2-Butylsulfamoyl-2-methyl-propionic acid 1H NMR (400 MHz- DMSO-d6): δppm 0.78 (3H, t, J = 7.3 Hz), 1.22 (2H, m), 1.35 (2H, m), 1.40 (6H, s),2.93 (2H, t, J = 6.9 Hz), 7.20 (1H, br s)

2-(2-Ethoxy-ethylsulfamoyl)-2-methyl- propionic acid 1H NMR (400 MHz-DMSO-d6): δ ppm 1.04 (3H, t, J = 7.1 Hz), 1.40 (6H, s), 3.07 (2H, t, J =6.4 Hz), 3.32 (2H, t, J = 6.4 Hz), 3.37 (2H, q, J = 7.1 Hz), 7.25 (1H,br s)

2-Methyl-2-(tetrahydro-pyran-4- ylsulfamoyl)-propionic acid 1H NMR (400MHz- DMSO-d6): δ ppm 1.35-1.46 (2H, m), 1.41 (6H, s), 1.67-1.74 (2H, m),3.16-3.25 (3H, m), 3.72-3.78 (2H, m), 7.28 (1H, br s)

2-Methyl-2-propylsulfamoyl-propionic acid 1H NMR (400 MHz- CHLOROFORM-d): δ ppm 0.97 (3H, t, J = 7.3 Hz), 1.63 (2H, m), 1.71 (6H, s), 3.23(2H, m), 4.63 (1H, br s)

2-(4,4-Difluoro-piperidine-1-sulfonyl)- 2-methyl-propionic acid 1H NMR(400 MHz- DMSO-d6): δ ppm 1.43 (6H, s), 1.90-2.00 (4H, m), 3.37 (4H, m)

2-(3,3-Difluoro-azetidine-1-sulfonyl)-2- methyl-propionic acid 1H NMR(400 MHz- CHLOROFORM- d): δ ppm 1.68 (6H, s), 4.37 (4H, t, J = 12.2 Hz)

(R)-2-(3-Fluoro-pyrrolidine-1-sulfonyl)- 2-methyl-propionic acid 1H NMR(400 MHz- CHLOROFORM- d): δ ppm 1.68 (6H, s), 1.93-2.30 (2H, m),3.57-3.77 (4H, m), 5.18-5.31 (1H, m)

2-Isopropylsulfamoyl-2-methyl- propionic acid 1H NMR (250 MHz-CHLOROFORM- d): δ ppm 1.11 (6H, d, J = 6.6 Hz), 1.52 (6H, s), 3.60 (1H,m)

2-(Butyl-methyl-sulfamoyl)-2-methyl- propionic acid 238

Step 5: Synthesis of2-(azetidine-1-sulfonyl)-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide

To a flask containing 2-(azetidine-1-sulfonyl)-2-methyl-propionic acid(75 mg, 0.36 mmol) is added thionyl chloride (2.5 mL). The resultingsolution is heated to 60° C. where it is maintained for 2 h. After thistime, the mixture is cooled to room temperature and concentrated underreduced pressure. The crude acid chloride is used without furtherpurification.

To a solution of 3-amino-5-tert-butylisoxazole (50 mg, 0.36 mmol) indichloromethane (1 mL) containing N,N-diisopropylethylamine (75 mL, 0.43mmol) at room temperature is added the acid chloride (˜0.36 mmol) as asolution in dichloromethane (1 mL). The reaction is stirred for 2 h andthen concentrated under reduced pressure. Purification by preparativeHPLC provides the title compound.

Examples listed in Table VII are prepared according to a similarprocedure.

TABLE VII Examples # Structure Name m/z [M + H⁺] 1

N-(5-tert-Butyl-isoxazol-3-yl)-2-dimethylsulfamoyl-2-methyl-propionamide 340 [M + Na⁺], 318 2

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-2-(morpholine-4-sulfonyl)- propionamide 373 3

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(2-methyl-piperidine-1-sulfonyl)-propionamide 372 4

N-(5-tert-Butyl-isoxazol-3-yl)-2-(isopropyl-methyl-sulfamoyl)-2-methyl-propionamide 346 5

2-(Azetidine-1-sulfonyl)-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide 352 [M + Na⁺], 330 6

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(pyrrolidine-1-sulfonyl)-propionamide 366 [M + Na⁺], 344 7

N-(5-tert-Butyl-isoxazol-3-yl)-2- cyclopropylsulfamoyl-2-methyl-propionamide 352 [M + Na⁺], 330 8

N-(5-tert-Butyl-isoxazol-3-yl)-2-cyclohexylsulfamoyl-2-methyl-propionamide 394 [M + Na⁺], 372 9

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(piperidine-1-sulfonyl)-propionamide 380 [M + Na⁺], 358 10

N-(5-tert-Butyl-isoxazol-3-yl)-2- cyclopentylsulfamoyl-2-methyl-propionamide 358 11

N-(5-tert-Butyl-isoxazol-3-yl)-2-(4-methoxy-piperidine-1-sulfonyl)-2-methyl- propionamide 410 [M + Na⁺], 388 12

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-cyclopropylsulfamoyl-2-methyl- propionamide 343 13

2-Methyl-2-(piperidine-1-sulfonyl)-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide 380 14

2-(4-Methoxy-piperidine-1-sulfonyl)-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)- propionamide 410 15

N-(5-tert-Butyl-isoxazol-3-yl)-2-isopropylsulfamoyl-2-methyl-propionamide 354 [M + Na⁺], 332 16

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-isopropylsulfamoyl-2-methyl-propionamide 345 17

2-Cyclopropylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide 352 18

2-Cyclohexylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide 394 19

2-Cyclopentylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide 402 [M + Na⁺], 380 20

N-(5-tert-Butyl-isoxazol-3-yl)-2- ethylsulfamoyl-2-methyl-propionamide318 21

N-(4-tert-Butyl-thiazol-2-yl)-2- ethylsulfamoyl-2-methyl-propionamide334 22

2-Ethylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide 340 23

2-Ethylsulfamoyl-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide 362 [M + Na⁺], 340 24

N-(5-tert-Butyl-isoxazol-3-yl)-2- butylsulfamoyl-2-methyl-propionamide346 25

2-Butylsulfamoyl-N-(4-tert-butyl-thiazol-2- yl)-2-methyl-propionamide362 26

2-Butylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide 368 27

2-Butylsulfamoyl-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide 390 [M + Na⁺], 368 28

N-(5-tert-Butyl-isoxazol-3-yl)-2-(2-ethoxy-ethylsulfamoyl)-2-methyl-propionamide 362 29

N-(4-tert-Butyl-thiazo1-2-yl)-2-(2-ethoxy-ethylsulfamoyl)-2-methyl-propionamide 378 30

2-(2-Ethoxy-ethylsulfamoyl)-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide 406 [M + Na⁺], 384 31

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)- propionamide 374 32

N-(4-tert-Butyl-thiazol-2-yl)-2-methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)- propionamide 390 33

2-Methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)-N-(5-trifluoromethyl-pyridin-2-yl)- propionamide 396 34

2-Methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)-N-(6-trifluoromethyl-pyridin-2-yl)- propionamide 418 [M + Na⁺], 396 35

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2- propylsulfamoyl-propionamide354 [M + Na⁺], 322 36

2-(2-Ethoxy-ethylsulfamoyl)-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide 406 [M + Na⁺], 384 37

N-(5-tert-Butyl-isoxazol-3-yl)-2-(4,4-difluoro-piperidine-1-sulfonyl)-2-methyl- propionamide 394 38

N-(5-tert-Butyl-isoxazol-3-yl)-2-(3,3-difluoro-azetidine-1-sulfonyl)-2-methyl-propionamide 366 39

(R)-N-(5-tert-Butyl-isoxazol-3-yl)-2-(3-fluoro-pyrrolidine-1-sulfonyl)-2-methyl- propionamide 362 40

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-morpholine-4-sulfonyl)-propionamide 360 41

N-(5-tert-Butyl-isoxazol-3-yl)-2-(butyl-methyl-sulfamoyl)-2-methyl-propionamide 360 42

2-(Azetidine-1-sulfonyl)-N-(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-2-methyl- propionamide 347 43

2-(Azetidine-1-sulfonyl)-N-[4-(4-chloro-phenyl)-thiazol-2-yl]-2-methyl-propionamide 400 44

2-(Azetidine-1-sulfonyl)-N-(4-tert-butyl-thiazol-2-yl)-2-methyl-propionamide 346 45

2-(Azetidine-1-sulfonyl)-N-[4-(4-fluoro-phenyl)-thiazol-2-yl]-2-methyl-propionamide 384 46

2-(Azetidine-1-sulfonyl)-N-(5-tert-butyl-4-methyl-thiazol-2-yl)-2-methyl-propionamide 360 47

2-(Azetidine-1-sulfonyl)-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide 330 48

2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-propyl-isoxazol-5-yl)-propionamide 316 49

2-(Azetidine-1-sulfonyl)-N-[3-(2,2-dimethyl-propyl)-isoxazol-5-yl]-2-methyl- propionamide 344 50

2-(Azetidine-1-sulfonyl)-N-benzothiazol-2-yl- 2-methyl-propionamide 34051

2-(Azetidine-1-sulfonyl)-N-(4-ethyl-pyridin-2- yl)-2-methyl-propionamide312 52

2-(Azetidine-1-sulfonyl)-2-methyl-N-(5-phenyl-[1,2,4]thiadiazol-3-yl)-propionamide 367 53

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-thiophen-2-yl-thiazol-2-yl)-propionamide 372 54

2-(Azetidine-1-sulfonyl)-N-(5-ethyl-4-phenyl-thiazol-2-yl)-2-methyl-propionamide 384 55

2-(Azetidine-1-sulfonyl)-N-(4-cyclohexyl-thiazol-2-yl)-2-methyl-propionamide 372 56

2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-trifluoromethyl-phenyl)-propionamide 351 57

2-(Azetidine-1-sulfonyl)-N-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl- propionamide 369 58

2-(Azetidine-1-sulfonyl)-N-(4-tert-butyl- phenyl)-2-methyl-propionamide339 59

2-(Azetidine-1-sulfonyl)-2-methyl-N- phenethyl-propionamide 311 60

2-(Azetidine-1-sulfonyl)-N-[2-(2-chloro-phenyl)-ethyl]-2-methyl-propionamide 345 61

2-(Azetidine-1-sulfonyl)-N-(3,3-dimethyl- butyl)-2-methyl-propionamide291 62

2-(Azetidine-1-sulfonyl)-N-(6-fluoro-benzothiazol-2-yl)-2-methyl-propionamide 358 63

2-(Azetidine-1-sulfonyl)-N-[2-(3-chloro-phenyl)-ethyl]-2-methyl-propionamide 345 64

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-trifluoromethyl-phenyl)-propionamide 351 65

2-(Azetidine-1-sulfonyl)-N-(3-tert-butyl- phenyl)-2-methyl-propionamide339 66

2-(Azetidine-1-sulfonyl)-N-(3-fluoro-4-trifluoromethyl-phenyl)-2-methyl- propionamide 369 67

2-(Azetidine-1-sulfonyl)-N-(4-tert-butyl-5-cyano-thiazol-2-yl)-2-methyl-propionamide 371 68

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-pyridin-3-yl-thiazol-2-yl)-propionamide 367 69

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-pyridin-2-yl-thiazol-2-yl)-propionamide 367 70

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-pyridin-4-yl-thiazol-2-yl)-propionamide 367 71

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-trifluoromethyl-thiazol-2-yl)-propionamide 358 72

2-(Azetidine-1-sulfonyl)-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide 352 73

2-(Azetidine-1-sulfonyl)-N-(3-sec-butyl-isoxazol-5-yl)-2-methyl-propionamide 330 74

2-(Azetidine-1-sulfonyl)-N-(3-isopropyl-isoxazol-5-yl)-2-methyl-propionamide 316 75

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-propionamide 344 76

2-[2-(Azetidine-1-sulfonyl)-2-methyl-propionylamino]-4-trifluoromethyl-thiazole-5- carboxylic acid ethylester 430 77

2-(Azetidine-1-sulfonyl)-N-(4,5-diphenyl-thiazol-2-yl)-2-methyl-propionamide 442 78

2-(Azetidine-1-sulfonyl)-N-(4,5-dimethyl-thiazol-2-yl)-2-methyl-propionamide 318 79

2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-phenyl-isoxazol-5-yl)-propionamide 350 80

2-(Azetidine-1-sulfonyl)-N-(4-cyclopropyl-thiazol-2-yl)-2-methyl-propionamide 330 81

2-(Azetidine-1-sulfonyl)-N-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl- propionamide 369 82

2-(Azetidine-1-sulfonyl)-N-(2-tert-butyl-pyridin-4-yl)-2-methyl-propionamide 340 83

2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-thiophen-2-yl-isoxazol-5-yl)-propionamide 356 84

2-(Azetidine-1-sulfonyl)-N-[4-(4-fluoro-phenyl)-5-methyl-thiazol-2-yl]-2-methyl- propionamide 398 85

N-(3-tert-Butyl-isoxazol-5-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamide 360 86

2-(Azetidine-1-sulfonyl)-2-methyl-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)-propionamide 350 87

2-Methyl-2-(morpholine-4-sulfonyl)-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)-propionamide 380 88

N-(5-tert-Butyl-[1,3,4]thiadiazol-2-yl)-2-methyl-2-(morpholine-4-sulfonyl)- propionamide 377 89

N-(3-tert-Butyl-isothiazol-5-yl)-2-(3-fluoro-pyrrolidine-1-sulfonyl)-2-methyl- propionamide 378 90

2-(3-Fluoro-pyrrolidine-1-sulfonyl)-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)- propionamide 384 91

N-(3-Cyclopentyl-isoxazol-5-yl)-2-(3 (R)-fluoro-pyrrolidine-1-sulfonyl)-2-methyl- propionamide 374 92

2-(3-Fluoro-pyrrolidine-1-sulfonyl)-2-methyl-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)- propionamide 382 93

2-(3-Fluoro-pyrrolidine-1-sulfonyl)-2-methyl-N-(4-trifluoromethyl-thiazol-2-yl)- propionamide 390Assessment of Biological Properties

The biological properties of the compounds of the formula I wereassessed using the assays described below.

A. Human CB1 and CB2 Receptor Binding:

Experimental Method:

CB2 membranes were purchased and made from HEK293 EBNA cells stablytransfected with human CB2 receptor cDNA (Perkin Elmer Life andAnalytical Sciences). CB1 membranes were isolated from HEK cells stablyco-transfected with human CB1 receptor and Gα16 cDNA's. The membranepreparation was bound to scintillation beads (Ysi-Poly-L-lysine SPAbeads, GE Healthcare) for 4 hours at room temperature in assay buffercontaining 50 mM Tris, pH 7.5, 2.5 mM EDTA, 5 mM MgCl₂, 0.8% fatty acidfree Bovine Serum Albumin Unbound membrane was removed by washing inassay buffer. Membrane-bead mixture was added to 96-well assay plates inthe amounts of 15 ug membrane per well (CB2) or 2.5 ug per well (CB1)and 1 mg SPA bead per well. Compounds were added to the membrane-beadmixture in dose-response concentrations ranging from 1×10⁻⁵M to 1×10⁻¹⁰M with 0.25% DMSO, final. The competition reaction was initiated withthe addition of ³H-CP55940 (Perkin Elmer Life and Analytical Sciences)at a final concentration of 1.5 nM (CB2) or 2.5 nM (CB1). The reactionwas incubated at room temperature for 18 hours and read on TopCount NXTplate reader. Total and non-specific binding was determined in theabsence and presence of 1.25 uM Win 55212 (Sigma). IC50 values for eachcompound were calculated as the concentration of compound that inhibitsthe specific binding of the radioactively labeled ligand to the receptorby 50% using the XLFit 4.1 four parameter logistic model. IC50 valueswere converted to inhibition constant (Ki) values using Cheng-Prusoffequation.

B. CB2R Mediated Modulation of cAMP Synthesis:

Compounds of the invention were evaluated for their CB2 agonist orinverse agonistic activity in accordance with the following experimentalmethod. Compounds which were shown to bind to CB2 by the binding assaydescribed above but which were not shown to exhibit CB2R-mediatedmodulation of cAMP synthesis by this assay were presumed to be CB2antagonists.

Experimental Method:

CHO cells expressing human CB2R (Euroscreen) were plated at a density of5000 cells per well in 384 well plates and incubated overnight at 37° C.After removing the media, the cells were treated with test compoundsdiluted in stimulation buffer containing 1 mM IBMX, 0.25% BSA and 10 uMForskolin. The assay was incubated for 30 minutes at 37° C. Cells werelysed and the cAMP concentration was measured using DiscoverX-XS cAMPkit, following the manufacturer's protocol. In this setting, agonistswill decrease forskolin induced production of cAMP while inverseagonists will further increase forskolin induced production of cAMP.EC50 of agonists were calculated as follows. The maximal amount of cAMPproduced by forskolin compared to the level of cAMP inhibited by 1 uMCP55940 is defined as 100%. The EC50 value of each test compound wasdetermined as the concentration at which 50% of the forskolin-stimulatedcAMP synthesis was inhibited. Data was analyzed using a four-parameterlogistic model. (Model 205 of XLfit 4.0).

C. CB1R Mediated Modulation of cAMP Synthesis:

Compounds of the invention were evaluated for their CB1 agonist orinverse agonistic activity in accordance with the following experimentalmethod. Compounds which were shown to bind to CB1 by the binding assaydescribed above but which were not shown to exhibit CB1R-mediatedmodulation of cAMP synthesis by this assay were presumed to be CB1antagonists.

Experimental Method:

CHO cells expressing human CB1R (Euroscreen) were plated at a density of5000 cells per well in 384 well plates and incubated overnight at 37° C.After removing the media, the cells were treated with test compoundsdiluted in stimulation buffer containing 1 mM IBMX, 0.25% BSA and 10 uMForskolin. The assay was incubated for 30 minutes at 37° C. Cells werelysed and the cAMP concentration was measured using DiscoverX-XS cAMPkit, following the manufacturer's protocol. In this setting, agonistswill decrease forskolin induced production of cAMP while inverseagonists will further increase forskolin induced production of cAMP.EC50 of agonists were calculated as follows. The maximal amount of cAMPproduced by forskolin compared to the level of cAMP inhibited by 1 uMCP55940 is defined as 100%. The EC50 value of each test compound wasdetermined as the concentration at which 50% of the forskolin-stimulatedcAMP synthesis was inhibited. Data was analyzed using a four-parameterlogistic model. (Model 205 of XLfit 4.0).

Compounds Having Agonist Activity

Through the use of the above described assays compounds were found toexhibit agonistic activity and thus to be particularly well suited forthe treatment of pain as well as for the treatment of inflammation.

Therapeutic Use

As can be demonstrated by the assays described above, the compounds ofthe invention are useful in modulating the CB2 receptor function. Byvirtue of this fact, these compounds have therapeutic use in treatingdisease-states and conditions mediated by the CB2 receptor function orthat would benefit from modulation of the CB2 receptor function.

As the compounds of the invention modulate the CB2 receptor function,they have very useful anti-inflammatory and immune-suppressive activityand they can be used in patients as drugs, particularly in the form ofpharmaceutical compositions as set forth below, for the treatment ofdisease-states and conditions.

As noted before, those compounds which are CB2 agonists can also beemployed for the treatment of pain.

The agonist compounds according to the invention can be used in patientsas drugs for the treatment of the following disease-states orindications that are accompanied by inflammatory processes:

-   -   (i) Lung diseases: e.g. asthma, bronchitis, allergic rhinitis,        emphysema, adult respiratory distress syndrome (ARDS), pigeon        fancier's disease, farmer's lung, chronic obstructive pulmonary        disease (COPD), asthma including allergic asthma (atopic or        non-atopic) as well as exercise-induced bronchoconstriction,        occupational asthma, viral- or bacterial exacerbation of asthma,        other non-allergic asthmas and “wheezy-infant syndrome”,        pneumoconiosis, including aluminosis, anthracosis, asbestosis,        chalicosis, ptilosis, siderosis, silicosis, tabacosis and        byssinosis;    -   (ii) Rheumatic diseases or autoimmune diseases or        musculoskeletal diseases: all forms of rheumatic diseases,        especially rheumatoid arthritis, acute rheumatic fever, and        polymyalgia rheumatica; reactive arthritis; rheumatic soft        tissue diseases; inflammatory soft tissue diseases of other        genesis; arthritic symptoms in degenerative joint diseases        (arthroses); tendinitis, bursitis, osteoarthritis, traumatic        arthritis; collagenoses of any genesis, e.g., systemic lupus        erythematosus, scleroderma, polymyositis, dermatomyositis,        Sjögren syndrome, Still disease, Felty syndrome; and        osteoporosis and other bone resorption diseases;    -   (iii) Allergic diseases: all forms of allergic reactions, e.g.,        angioneurotic edema, hay fever, insect bites, allergic reactions        to drugs, blood derivatives, contrast agents, etc., anaphylactic        shock (anaphylaxis), urticaria, angioneurotic edema, and contact        dermatitis;    -   (iv) Vascular diseases: panarteritis nodosa, polyarteritis        nodosa, periarteritis nodosa, arteritis temporalis, Wegner        granulomatosis, giant cell arthritis, atherosclerosis,        reperfusion injury and erythema nodosum;    -   (v) Dermatological diseases: e.g. dermatitis, psoriasis;        sunburn, burns, eczema;    -   (vi) Renal diseases: e.g. nephrotic syndrome; and all types of        nephritis, e.g., glomerulonephritis; pancreatits;    -   (vii) Hepatic diseases: e.g. acute liver cell disintegration;        acute hepatitis of various genesis, e.g., viral, toxic,        drug-induced; and chronically aggressive and/or chronically        intermittent hepatitis;    -   (viii) Gastrointestinal diseases: e.g. inflammatory bowel        diseases, irritable bowel syndrome, regional enteritis (Crohns        disease), colitis ulcerosa; gastritis; aphthous ulcer, celiac        disease, regional ileitis, gastroesophageal reflux disease;    -   (ix) Neuroprotection: e.g. in the treatment of neurodegeneration        following stroke; cardiac arrest; pulmonary bypass; traumatic        brain injury; spinal cord injury or the like;    -   (x) Eye diseases: allergic keratitis, uveitis, or iritis;        conjunctivitis; blepharitis; neuritis nervi optici; choroiditis;        glaucoma and sympathetic ophthalmia;    -   (xi) Diseases of the ear, nose, and throat (ENT) area: e.g.        tinnitus; allergic rhinitis or hay fever; otitis externa; caused        by contact eczema, infection, etc.; and otitis media;    -   (xii) Neurological diseases: e.g. brain edema, particularly        tumor-related brain edema; multiple sclerosis; acute        encephalomyelitis; meningitis; acute spinal cord injury; trauma;        dementia, particularly degenerative dementia (including senile        dementia, Alzheimer's disease; Parkinson's disease and        Creutzfeldt-Jacob disease; Huntington's chorea, Pick's disease;        motor neuron disease), vascular dementia (including        multi-infarct dementia) as well as dementia associated with        intracranial space occupying lesions; infections and related        conditions (including HIV infection); Guillain-Barre syndrome;        myasthenia gravis, stroke; and various forms of seizures, e.g.,        nodding spasms;    -   (xiii) Blood diseases: acquired hemolytic anemia; aplastic        anemia, and idiopathic thrombocytopenia;    -   (xiv) Tumor diseases: acute lymphatic leukemia; Hodgkin's        disease, malignant lymphoma; lymphogranulomatoses;        lymphosarcoma; solid malignant tumors; extensive metastases;    -   (xv) Endocrine diseases: endocrine opthalmopathy; endocrine        orbitopathia; thyrotoxic crisis; Thyroiditis de Quervain;        Hashimoto thyroiditis; Morbus Basedow; granulomatous        thyroiditis; struma lymphomatosa; and Graves disease; type I        diabetes (insulin-dependent diabetes);    -   (xvi) Organ and tissue transplantations and graft-versus-host        diseases;    -   (xvii) Severe states of shock, e.g., septic shock, anaphylactic        shock, and systemic inflammatory response syndrome (SIRS);    -   (xviii) Acute pain such as dental pain, perioperative,        post-operative pain, traumatic pain, muscle pain, pain in burned        skin, sun burn, trigeminal neuralgia, sun burn; spasm of the        gastrointestinal tract or uterus, colics;    -   (xix) Visceral pain such as pain associated with chronic pelvic        pain, pancreatitis, peptic ulcer, interstitial cystitis, renal        colic, angina, dysmenorrhoea, menstruation, gynaecological pain,        irritable bowel syndrome (IBS), non-ulcer dyspepsia, non-cardiac        chest pain, myocardial ischemia;    -   (xx) Neuropathic pain such as low back pain, non-herpetic        neuralgia, post herpetic neuralgia, diabetic neuropathy, nerve        injury, acquired immune deficiency syndrome (AIDS) related        neuropathic pain, head trauma, painful traumatic mononeuropathy,        toxin and chemotherapy induced pain, phantom limb pain, painful        polyneuropathy, thalamic pain syndrome, post-stroke pain,        central nervous system injury, post surgical pain, stump pain,        repetitive motion pain, pain induced by post mastectomy        syndrome, multiple sclerosis, root avulsions, postthoracotomy        syndrome, neuropathic pain associated hyperalgesia and        allodynia.    -   (xxi) Inflammatory/nociceptive pain induced by or associated        with disorders such as osteoarthritis, rheumatoid arthritis,        rheumatic disease, teno-synovitis, gout, vulvodynia, myofascial        pain (muscular injury, fibromyalgia), tendonitis,        osteoarthritis, juvenile arthritis, spondylitis, gouty        arthritis, psoriatic arthritis, muscoskeletal pain,        fibromyalgia, sprains and strains, sympathetically maintained        pain, myositis, pain associated with migraine, toothache,        influenza and other viral infections such as the common cold,        rheumatic fever, systemic lupus erythematosus;    -   (xxii) Cancer pain induced by or associated with tumors such as        lymphatic leukemia; Hodgkin's disease, malignant lymphoma;        lymphogranulomatoses; lymphosarcoma; solid malignant tumors;        extensive metastases;    -   (xxiii) Headache such as cluster headache, migraine with and        without aura, tension type headache, headache with different        origins, headache disorders including prophylactic and acute        use;    -   (xxiv) various other disease-states or conditions including,        restenosis following percutaneous transluminal coronary        angioplasty, acute and chronic pain, atherosclerosis,        reperfusion injury, congestive heart failure, myocardial        infarction, thermal injury, multiple organ injury secondary to        trauma, necrotizing enterocolitis and syndromes associated with        hemodialysis, leukopheresis, and granulocyte transfusion,        sarcoidosis, gingivitis, pyrexia, edema resulting from trauma        associated with burns, sprains or fracture, cerebral oedema and        angioedema, Diabetes such as diabetic vasculopathy, diabetic        neuropathy, diabetic retinopathy, post capillary resistance or        diabetic symptoms associated with insulitis (e.g. hypergiycemia,        diuresis, proteinuria and increased nitrite and kallikrein        urinary excretion).

Other indications include: epilepsy, septic shock e.g. asantihypovolemic and/or antihypotensive agents, cancer, sepsis,osteoporosis, benign prostatic hyperplasia and hyperactive bladder,pruritis, vitiligo, general gastrointestinal disorders, disturbances ofvisceral motility at respiratory, genitourinary, gastrointestinal orvascular regions, wounds, burns, tissue damage and postoperative fever,syndromes associated with Itching.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals, including mammals, rodents, and the like.

For treatment of the above-described diseases and conditions, atherapeutically effective dose will generally be in the range from about0.01 mg to about 100 mg/kg of body weight per dosage of a compound ofthe invention; preferably, from about 0.1 mg to about 20 mg/kg of bodyweight per dosage. For example, for administration to a 70 kg person,the dosage range would be from about 0.7 mg to about 7000 mg per dosageof a compound of the invention, preferably from about 7.0 mg to about1400 mg per dosage. Some degree of routine dose optimization may berequired to determine an optimal dosing level and pattern. The activeingredient may be administered from 1 to 6 times a day.

General Administration and Pharmaceutical Compositions

When used as pharmaceuticals, the compounds of the invention aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared using procedures well known in thepharmaceutical art and comprise at least one compound of the invention.The compounds of the invention may also be administered alone or incombination with adjuvants that enhance stability of the compounds ofthe invention, facilitate administration of pharmaceutical compositionscontaining them in certain embodiments, provide increased dissolution ordispersion, increased inhibitory activity, provide adjunct therapy, andthe like. The compounds according to the invention may be used on theirown or in conjunction with other active substances according to theinvention, optionally also in conjunction with other pharmacologicallyactive substances. In general, the compounds of this invention areadministered in a therapeutically or pharmaceutically effective amount,but may be administered in lower amounts for diagnostic or otherpurposes.

Administration of the compounds of the invention, in pure form or in anappropriate pharmaceutical composition, can be carried out using any ofthe accepted modes of administration of pharmaceutical compositions.Thus, administration can be, for example, orally, buccally (e.g.,sublingually), nasally, parenterally, topically, transdermally,vaginally, or rectally, in the form of solid, semi-solid, lyophilizedpowder, or liquid dosage forms, such as, for example, tablets,suppositories, pills, soft elastic and hard gelatin capsules, powders,solutions, suspensions, or aerosols, or the like, preferably in unitdosage forms suitable for simple administration of precise dosages. Thepharmaceutical compositions will generally include a conventionalpharmaceutical carrier or excipient and a compound of the invention asthe/an active agent, and, in addition, may include other medicinalagents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles,or combinations thereof. Such pharmaceutically acceptable excipients,carriers, or additives as well as methods of making pharmaceuticalcompositions for various modes or administration are well-known to thoseof skill in the art. The state of the art is evidenced, e.g., byRemington: The Science and Practice of Pharmacy, 20th Edition, A.Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook ofPharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995;Handbook of Pharmaceutical Excipients, A.H. Kibbe (ed.), AmericanPharmaceutical Ass'n, 2000; H. C. Ansel and N. G. Popovish,Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea andFebiger, 1990; each of which is incorporated herein by reference intheir entireties to better describe the state of the art.

As one of skill in the art would expect, the forms of the compounds ofthe invention utilized in a particular pharmaceutical formulation willbe selected (e.g., salts) that possess suitable physical characteristics(e.g., water solubility) that is required for the formulation to beefficacious.

The invention claimed is:
 1. A method of treating pain comprisingadministering to a patient a therapeutically effective amount of acompound of the formula (I)

wherein, R¹ is C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl-C₀₋₂ alkyl- orheterocycle-C₀₋₂ alkyl- wherein the heterocycle is chosen fromtetrahydropyranyl, tetrahydrofuranyl, dioxanyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, piperidinyl, pyrrolidinyl,tetrahydrothienyl, tetrahydrothiopyranyl,1,1-dioxo-tetrahydrothiopyranyl, imidazolidinyl, pyrazolidinyl oroxetanyl, each R¹ is optionally substituted with 1 to 3 substituentschosen from halogen, C₁₋₅ alkyl, C₃₋₁₀ cycloalkyl, hydroxy or C₁₋₆alkoxy; R² is hydrogen or C₁₋₅ alkyl; or R¹ and R² together with the Natom to which they are attached form a 3- to 6-membered heterocyclicring optionally substituted with 1-3 substituents chosen from C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl, hydroxyl, C₁₋₃alkylaminocarbonyl, C₁₋₃ dialkylaminocarbonyl, C₁₋₃ alkylcarbonyl, C₁₋₃alkyl sulfonyl or halogen; R³ is methyl, ethyl, or isopropyl; R⁴ is H ormethyl; or R³ and R⁴ together with the carbon they are attached to forma 3-4 membered cycloalkyl ring; R⁵ is furanyl, pyranyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, oxazolyl, imidazolyl, thienyl,pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoxazolyl, thiazolyl,thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, pyridinyl orbenzothiazolyl each optionally independently substituted with 1 to 3substituents chosen from C₁₋₆ alkyl, C₁₋₅ alkoxycarbonyl, cyano orhalogen, each R⁵ or it's substituents where possible are optionallypartially or fully halogenated; or a pharmaceutically acceptable saltthereof.
 2. The method according to claim 1 wherein, R¹ is C₁₋₅ alkyl,C₃₋₆ cycloalkyl-C₀₋₂ alkyl- or heterocycle-C₀₋₂ alkyl- wherein theheterocycle is chosen from tetrahydropyranyl, tetrahydrofuranyl,dioxanyl, thiomorpholinyl, 1,1-dioxo-1λ⁶-thiomorpholinyl, piperidinyl,pyrrolidinyl, tetrahydrothienyl, tetrahydrothiopyranyl,1,1-dioxo-tetrahydrothiopyranyl, imidazolidinyl, pyrazolidinyl,oxetanyl, or morpholinyl, each R¹ is optionally independentlysubstituted with 1 to 3 substituents chosen from halogen, C₁₋₅ alkyl,C₃₋₆ cycloalkyl, hydroxy or C₁₋₆ alkoxy; R¹ and R² together with the Natom to which they are attached form morpholinyl, piperidinyl,azetidinyl, pyrrolidinyl homopiperidinyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholinyl or piperazinyl, each optionallysubstituted with 1-3 substituents chosen from C₁₋₃ alkyl, C₁₋₃ alkoxy,C₃₋₆ cycloalkyl, C₁₋₃ alkylaminocarbonyl, C₁₋₃ dialkylaminocarbonyl,C₁₋₃ alkylcarbonyl, C₁₋₃ alkyl sulfonyl or halogen; R⁵ is furanyl,pyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl,imidazolyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, triazolyl, pyridinyl orbenzothiazolyl each R⁵ substituent is further optionally substitutedwith 1 to 3 substituents chosen from C₁₋₅ alkyl, C₁₋₅ alkoxycarbonyl,cyano or halogen, each R⁵ or it's substituents where possible areoptionally partially or fully halogenated.
 3. The method according toclaim 2 wherein, R¹ is C₁₋₅ alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylmethyl, tetrahydropyranyl, tetrahydrofuranyl or morpholinyl,each optionally independently substituted with 1 to 3 substituentschosen from halogen, C₁₋₃ alkyl, C₃₋₆ cycloalkyl or C₁₋₃ alkoxy; R⁵ isfuranyl, pyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,oxazolyl, imidazolyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, triazolyl,pyridinyl or benzothiazolyl each R⁵ substituent is further optionallysubstituted with 1 to 3 substituents chosen from C₁₋₅ alkyl, C₁₋₅alkoxycarbonyl, cyano or halogen, each R⁵ or it's substituents wherepossible are optionally partially or fully halogenated.
 4. The methodaccording to claim 3 wherein, R¹ is C₁₋₅ alkyl, C₃₋₆ cycloalkyl,cyclohexylmethyl or tetrahydropyranyl, each optionally independentlysubstituted with 1 to 3 substituents chosen from halogen, C₁₋₃ alkyl,C₃₋₆ cycloalkyl or C₁₋₄ alkoxy; R¹ and R² together with the N atom towhich they are attached form morpholinyl, piperidinyl, azetidinyl orpyrrolidinyl each optionally substituted with 1-3 substituents chosenfrom C₁₋₃ alkyl, C₁₋₃ alkoxy, C₃₋₆ cycloalkyl, C₁₋₃ alkylaminocarbonyl,C₁₋₃ dialkylaminocarbonyl, C₁₋₃ alkylcarbonyl, C₁₋₃ alkyl sulfonyl orhalogen.
 5. The method according to claim 4 wherein, R¹ is C₁₋₅ alkyl,C₃₋₆ cycloalkyl or tetrahydropyranyl, each optionally independentlysubstituted with 1 to 3 substituents chosen from halogen, C₁₋₃ alkyl,C₁₋₃ alkoxy or C₃₋₆ cycloalkyl.
 6. A method of treating pain comprisingadministering to a patient a therapeutically effective amount of acompound of the formula (I),

wherein for the formula (I)

is chosen members of column A in Table I, and

is chosen members of column B in Table I: TABLE I A B

or a pharmaceutically acceptable salt thereof.
 7. A compound chosen fromN-(5-tert-Butyl-isoxazol-3-yl)-2-dimethylsulfamoyl-2-methyl-propionamideN-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(2-methyl-piperidine-1-sulfonyl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-(isopropyl-methyl-sulfamoyl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(pyrrolidine-1-sulfonyl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-cyclopropylsulfamoyl-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-cyclohexylsulfamoyl-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(piperidine-1-sulfonyl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-cyclopentylsulfamoyl-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-(4-methoxy-piperidine-1-sulfonyl)-2-methyl-propionamideN-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-cyclopropylsulfamoyl-2-methyl-propionamide2-Methyl-2-(piperidine-1-sulfonyl)-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide2-(4-Methoxy-piperidine-1-sulfonyl)-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-isopropylsulfamoyl-2-methyl-propionamideN-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-isopropylsulfamoyl-2-methyl-propionamide2-Cyclopropylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide2-Cyclohexylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide2-Cyclopentylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-ethylsulfamoyl-2-methyl-propionamideN-(4-tert-Butyl-thiazol-2-yl)-2-ethylsulfamoyl-2-methyl-propionamide2-Ethylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide2-Ethylsulfamoyl-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-butylsulfamoyl-2-methyl-propionamide2-Butylsulfamoyl-N-(4-tert-butyl-thiazol-2-yl)-2-methyl-propionamide2-Butylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide2-Butylsulfamoyl-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-(2-ethoxy-ethylsulfamoyl)-2-methyl-propionamideN-(4-tert-Butyl-thiazol-2-yl)-2-(2-ethoxy-ethylsulfamoyl)-2-methyl-propionamide2-(2-Ethoxy-ethylsulfamoyl)-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)-propionamideN-(4-tert-Butyl-thiazol-2-yl)-2-methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)-propionamide2-Methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide2-Methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)-N-(6-trifluoromethyl-pyridin-2-yl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-propylsulfamoyl-propionamide2-(2-Ethoxy-ethylsulfamoyl)-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-(4,4-difluoro-piperidine-1-sulfonyl)-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-(3,3-difluoro-azetidine-1-sulfonyl)-2-methyl-propionamide(R)-N-(5-tert-Butyl-isoxazol-3-yl)-2-(3-fluoro-pyrrolidine-1-sulfonyl)-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-(butyl-methyl-sulfamoyl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-[4-(4-chloro-phenyl)-thiazol-2-yl]-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(4-tert-butyl-thiazol-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-[4-(4-fluoro-phenyl)-thiazol-2-yl]-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(5-tert-butyl-4-methyl-thiazol-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-propyl-isoxazol-5-yl)-propionamide2-(Azetidine-1-sulfonyl)-N-[3-(2,2-dimethyl-propyl)-isoxazol-5-yl]-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-benzothiazol-2-yl-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(4-ethyl-pyridin-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(5-phenyl-[1,2,4]thiadiazol-3-yl)-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-thiophen-2-yl-thiazol-2-yl)-propionamide2-(Azetidine-1-sulfonyl)-N-(5-ethyl-4-phenyl-thiazol-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(4-cyclohexyl-thiazol-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-trifluoromethyl-phenyl)-propionamide2-(Azetidine-1-sulfonyl)-N-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(4-tert-butyl-phenyl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-phenethyl-propionamide2-(Azetidine-1-sulfonyl)-N-[2-(2-chloro-phenyl)-ethyl]-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(3,3-dimethyl-butyl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(6-fluoro-benzothiazol-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-[2-(3-chloro-phenyl)-ethyl]-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-trifluoromethyl-phenyl)-propionamide2-(Azetidine-1-sulfonyl)-N-(3-tert-butyl-phenyl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(3-fluoro-4-trifluoromethyl-phenyl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(4-tert-butyl-5-cyano-thiazol-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-pyridin-3-yl-thiazol-2-yl)-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-pyridin-2-yl-thiazol-2-yl)-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-pyridin-4-yl-thiazol-2-yl)-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-trifluoromethyl-thiazol-2-yl)-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide2-(Azetidine-1-sulfonyl)-N-(3-sec-butyl-isoxazol-5-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(3-isopropyl-isoxazol-5-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-propionamide2-[2-(Azetidine-1-sulfonyl)-2-methyl-propionylamino]-4-trifluoromethyl-thiazole-5-carboxylicacid ethyl ester2-(Azetidine-1-sulfonyl)-N-(4,5-diphenyl-thiazol-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(4,5-dimethyl-thiazol-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-phenyl-isoxazol-5-yl)-propionamide2-(Azetidine-1-sulfonyl)-N-(4-cyclopropyl-thiazol-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(2-tert-butyl-pyridin-4-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-thiophen-2-yl-isoxazol-5-yl)-propionamide2-(Azetidine-1-sulfonyl)-N-[4-(4-fluoro-phenyl)-5-methyl-thiazol-2-yl]-2-methyl-propionamideN-(3-tert-Butyl-isoxazol-5-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)-propionamide2-Methyl-2-(morpholine-4-sulfonyl)-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)-propionamideN-(5-tert-Butyl-[1,3,4]thiadiazol-2-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamideN-(3-tert-Butyl-isothiazol-5-yl)-2-(3-fluoro-pyrrolidine-1-sulfonyl)-2-methyl-propionamide2-(3-Fluoro-pyrrolidine-1-sulfonyl)-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamideN-(3-Cyclopentyl-isoxazol-5-yl)-2-(3(R)-fluoro-pyrrolidine-1-sulfonyl)-2-methyl-propionamide2-(3-Fluoro-pyrrolidine-1-sulfonyl)-2-methyl-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)-propionamideor2-(3-Fluoro-pyrrolidine-1-sulfonyl)-2-methyl-N-(4-trifluoromethyl-thiazol-2-yl)-propionamideor a pharmaceutically acceptable salt thereof.
 8. A compound chosen fromN-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(2-methyl-piperidine-1-sulfonyl)-propionamide2-(Azetidine-1-sulfonyl)-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(pyrrolidine-1-sulfonyl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-cyclopropylsulfamoyl-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-cyclohexylsulfamoyl-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(piperidine-1-sulfonyl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-cyclopentylsulfamoyl-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-butylsulfamoyl-2-methyl-propionamide2-Butylsulfamoyl-N-(4-tert-butyl-thiazol-2-yl)-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-propylsulfamoyl-propionamideN-(4-tert-Butyl-thiazol-2-yl)-2-methyl-2-(methyl-phenyl-sulfamoyl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-(4,4-difluoro-piperidine-1-sulfonyl)-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-(3,3-difluoro-azetidine-1-sulfonyl)-2-methyl-propionamide(R)-N-(5-tert-Butyl-isoxazol-3-yl)-2-(3-fluoro-pyrrolidine-1-sulfonyl)-2-methyl-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamideN-(5-tert-Butyl-isoxazol-3-yl)-2-(butyl-methyl-sulfamoyl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-[4-(4-chloro-phenyl)-thiazol-2-yl]-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(4-tert-butyl-thiazol-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-[4-(4-fluoro-phenyl)-thiazol-2-yl]-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(5-tert-butyl-4-methyl-thiazol-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-benzothiazol-2-yl-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(5-phenyl-[1,2,4]thiadiazol-3-yl)-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-thiophen-2-yl-thiazol-2-yl)-propionamide2-(Azetidine-1-sulfonyl)-N-(5-ethyl-4-phenyl-thiazol-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(4-cyclohexyl-thiazol-2-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(4-tert-butyl-phenyl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(3-tert-butyl-phenyl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(3-sec-butyl-isoxazol-5-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(3-isopropyl-isoxazol-5-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-propionamide2-(Azetidine-1-sulfonyl)-N-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-(2-tert-butyl-pyridin-4-yl)-2-methyl-propionamide2-(Azetidine-1-sulfonyl)-N-[4-(4-fluoro-phenyl)-5-methyl-thiazol-2-yl]-2-methyl-propionamideN-(3-tert-Butyl-isoxazol-5-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamide2-(Azetidine-1-sulfonyl)-2-methyl-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)-propionamide2-Methyl-2-(morpholine-4-sulfonyl)-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)-propionamideN-(3-tert-Butyl-isothiazol-5-yl)-2-(3-fluoro-pyrrolidine-1-sulfonyl)-2-methyl-propionamideor2-(3-Fluoro-pyrrolidine-1-sulfonyl)-2-methyl-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)-propionamideor a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim
 7. 10. The method according to claim 1 wherein thepain is acute pain, visceral pain, neuropathic pain, nociceptive pain orcancer pain.